Hypnotics (also see Chapter 10 )

Propofol

Propofol is best administered by continuous infusion and is presently the most common intravenous anesthetic used for TIVA and sedation. Plasma concentrations necessary during surgery and for awakening have been established (see Table 12-6 ).^{[39] [40] [41] [92] [93]} To obtain a plasma level of 3 to 4 µg/mL, a four-stage infusion scheme can be used. This scheme consists of a loading dose of 1 mg/kg over a period of 20 seconds, followed by 170 µg/kg/min (10 mg/kg/hr) for 10 minutes, then 130 µg/kg/min (8 mg/kg/hr) for 10 minutes, and 100 µg/kg/min (6 mg/kg/hr) thereafter. More simply, a loading dose of 1 to 2 mg/kg can be followed by an initial infusion of 150 to 200 µg/kg/min, which is then titrated down to about 100 µg/kg/min. For short surgical procedures, generally higher average infusion rates are required, but for longer procedures, the average infusion rate is 100 to 150 µg/kg/min when combined with nitrous oxide. The reader can also construct propofol infusion regimens for other target concentrations from the nomogram in Figure 12-15 .

When propofol is given with an opioid (rather than nitrous oxide) as part of a TIVA technique, the infusion rate of propofol remains similar to that required with nitrous oxide (i.e., an initial induction dose followed by a decreasing infusion rate of 150 to 100 µg/kg/min). Propofol has been combined with alfentanil (loading dose, 10 to 25 µg/kg; maintenance infusion, 0.5 to 1 µg/kg/min), fentanyl (loading dose, 2 to 5 µg/kg; maintenance infusion, 0.02 to 0.06 µg/kg/min), sufentanil (loading dose, 0.2 to 0.5 µg/kg; maintenance infusion, 0.005 to 0.03 µg/kg/min), and remifentanil (loading dose, 1 µg/kg; maintenance infusion, 0.05 to 0.4 µg/kg/min) for total intravenous anesthesia. The required infusion rate of propofol during anesthesia demonstrates a negative correlation with age; that is, elderly patients need lower infusion rates.

For sedation during regional or topical anesthesia, an initial loading infusion of 0.5 mg/kg is given over a 5-minute period, followed by a maintenance infusion of 25 to 75 µg/kg/min. Another technique used by the authors is to give bolus doses of 0.2 mg/kg every 1.5 to 3 minutes until the desired level of sedation is achieved.

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Propofol has been used for up to 2 weeks for continuous sedation of patients in intensive care units.^[94] In critically ill patients, a loading dose may not be desirable, and therefore an infusion can be started at 25 to 50 µg/kg/min. This rate is subsequently titrated to the desired level of sedation.

Thiopental

Thiopental is rarely administered by infusion for the maintenance of surgical anesthesia because the context-sensitive half-time is prolonged when an infusion lasting more than just a brief duration is used. Thiopental has been successfully administered by infusion for short body surface procedures in combination with fentanyl.^[95] An initial loading dose of 2 to 4 mg/kg is followed by an infusion of 200 to 300 µg/kg/min for the first 20 minutes and 30 to 70 µg/kg/min thereafter. For sedation, an initial loading dose of 2 to 4 mg/kg is followed by an infusion of 30 to 80 µg/kg/min. When thiopental is administered by infusion, its metabolism results in the formation of pentobarbital. It is uncertain, however, whether formation of this barbiturate is of clinical significance.

Methohexital

Methohexital (unlike thiopental) can be used effectively by infusion for the maintenance of anesthesia during surgical procedures lasting up to 2 hours. A loading (induction) dose of 1 to 2 mg/kg is followed by an infusion of 50 to 150 µg/kg/min. Methohexital (at these infusion rates) can be combined with 66% nitrous oxide, an opioid, or both. Methohexital may also be administered by infusion for sedation. A loading dose of 0.5 to 1 mg/kg given over a period of 5 to 10 minutes followed by an infusion of 15 to 25 µg/kg/min usually provides an adequate level of sedation.

Etomidate

The use of etomidate by infusion is controversial (see Chapter 10 ). Most infusions with etomidate for general anesthesia are designed to provide a plasma etomidate concentration of 500 ng/mL.^[96] This concentration may be achieved with either a two- or a three-stage infusion scheme. In the two-stage scheme, etomidate is infused at 100 µg/kg/min for a period of 10 minutes and then at 10 µg/kg/min. In the three-stage regimen, etomidate is infused at 100 µg/kg/min for 3 minutes, 20 µg/kg/min for 27 minutes, and 10 µg/kg/min thereafter. Etomidate is combined with nitrous oxide and usually an opioid given either intermittently or by continuous infusion. Etomidate plus fentanyl (loading dose, 2 to 3 µg/kg; maintenance infusion, 0.02 to 0.06 µg/kg/min) or alfentanil (loading dose, 10 to 20 µg/kg; maintenance infusion, 0.5 to 1 µg/kg/min) can be combined to provide total intravenous anesthesia. The etomidate infusion can usually be terminated 10 to 15 minutes before the anticipated end of the surgical procedure. Etomidate has been administered by infusion for cardiac surgery. An initial loading dose (used for induction) is followed by an infusion of etomidate at 20 µg/kg/min. Such administration results in a plasma level of 550 to 900 ng/mL. The use of etomidate for prolonged sedation is contraindicated, but it can be administered for brief periods of sedation (i.e., for regional anesthesia). For sedation, a loading dose of 15 to 20 µg/kg/min for 10 minutes is followed by a maintenance infusion of 2.5 to 7.5 µg/kg/min.

Ketamine

Ketamine, although it possesses both hypnotic and analgesic properties, as well as suitable pharmacokinetics, is not a popular agent for maintenance of general anesthesia because of the psychotomimetic action of the currently available racemic mixture. The impact of ketamine on postoperative analgesia may again increase its use, especially at low doses.

When combined with a benzodiazepine, ketamine can provide suitable anesthesia (with or without nitrous oxide). The loading (induction) dose is 1 to 2 mg/kg followed by an infusion of 10 to 50 µg/kg/min.^[97] In the absence of nitrous oxide and for more invasive surgery, higher infusion rates of 30 to 100 µg/kg/min may be necessary. Ketamine has also been administered by infusion during cardiac surgery at similar infusion rates. An infusion of ketamine is also useful for analgesia or sedation, or for both. The loading dose can be reduced to 0.2 to 0.75 mg/kg and the infusion to 5 to 20 µg/kg/min. Ketamine has been successfully used with propofol for a TIVA technique. The ketamine infusion consists of a loading dose of 1 to 3 mg/kg followed by an infusion of 5 to 20 µg/kg/min. The propofol infusion is the same regimen used when propofol is combined with nitrous oxide. Like alfentanil, ketamine has been mixed with propofol to provide a single-syringe TIVA technique.

Midazolam

Midazolam can be administered by infusion for sedation or for provision of the hypnotic component of a balanced anesthetic.^[98] The effects of an opioid plus a benzodiazepine appear to be synergistic rather than additive for both loss of consciousness and anesthesia.^{[69] [99]} The loading (induction) dose of midazolam can therefore be reduced to 0.05 to 0.1 mg/kg when combined with fentanyl (2 to 5 µg/kg) or alfentanil (10 to 25 µg/kg). The midazolam maintenance infusion rate during surgical anesthesia can then be titrated to between 0.25 and 1 µg/kg/min with either fentanyl (maintenance infusion, 0.02 to 0.06 µg/kg/min) or alfentanil (maintenance infusion, 0.5 to 1.5 µg/kg/min). Nitrous oxide, if added to the aforementioned combinations, further decreases the required infusion rates of both midazolam and the opioid. For cardiac surgery, similar doses of midazolam can be combined with slightly larger doses of the chosen opioid.^[100] For sedation, a loading dose of 0.02 to 0.1 mg/kg of midazolam is administered. This is best given as 10-µg/kg doses until the desired level of sedation is achieved. The maintenance infusion is then titrated to between 0.25 and 1 µg/kg/min. At the termination of a prolonged (days) infusion, the development of a benzodiazepine withdrawal syndrome is possible. Therefore, the infusion might need to be slowly tapered, or a long-acting benzodiazepine may need to be given.